DESCRIPTION (Verbatim from applicant?s abstract): Although gene therapy been shown to be a promising strategy for excitotoxic insults in the brain, currently used vectors do not express functional protein soon enough after insult to target the earliest events reading to necrotic neuronal injury. This proposal tests a novel strategy: constitutive expression of a potentially protective protein whose activity would be activated by insult. Seizures are, by definition, excitotoxic, and decreasing such excitation might be neuroprotective. This might be accomplished by hyperpolarizing excited neurons via outwardly rectifying potassium (K+) channels, thus prolonging the recovery phase of the action potential and/or shortening spike duration. The protective effects of a Ca2+-regulated or a voltage-gated K+ channel will be explored. In pilot data we have shown that both protect in primary hippocampal cultures against glutamate, staurosporine, and sodium cyanide. We will extend these findings by testing more insults as well as exploring the extent to which protection targets necrosis vs. apoptosis. In vivo studies will not only examine whether there is sparing of neuron number, but of function as well (using electrophysiological and behavioral endpoints). Finally, we will examine the activity of these channels in healthy neurons and, if they are active, test their effects on normal learning and memory.